Reconstituted Extracellular Vesicles from Human Platelets Decrease Viral Myocarditis in Mice

Danielle J. Beetler; Katelyn A. Bruno; Molly M. Watkins; Vivian Xu; Isha Chekuri; Presley Giresi; Damian N. Di Florio; Emily R. Whelan; Brandy H. Edenfield; Sierra A. Walker; Andrea C. Morales-Lara; Anneliese R. Hill; Angita Jain; Matthew E. Auda; Logan P. Macomb; Kathryn A. Shapiro; Kevin C. Keegan; Joy Wolfram; Atta Behfar; Paul G. Stalboerger; Andre Terzic; Houssam Farres; Leslie T. Cooper; De Lisa Fairweather

doi:10.1002/smll.202303317

Reconstituted Extracellular Vesicles from Human Platelets Decrease Viral Myocarditis in Mice

Danielle J. Beetler, Katelyn A. Bruno, Molly M. Watkins, Vivian Xu, Isha Chekuri, Presley Giresi, Damian N. Di Florio, Emily R. Whelan, Brandy H. Edenfield, Sierra A. Walker, Andrea C. Morales-Lara, Anneliese R. Hill, Angita Jain, Matthew E. Auda, Logan P. Macomb, Kathryn A. Shapiro, Kevin C. Keegan, Joy Wolfram, Atta Behfar, Paul G. StalboergerAndre Terzic, Houssam Farres, Leslie T. Cooper, De Lisa Fairweather

Research output: Contribution to journal › Article › peer-review

Abstract

Patients with viral myocarditis are at risk of sudden death and may progress to dilated cardiomyopathy (DCM). Currently, no disease-specific therapies exist to treat viral myocarditis. Here it is examined whether reconstituted, lyophilized extracellular vesicles (EVs) from platelets from healthy men and women reduce acute or chronic myocarditis in male mice. Human-platelet-derived EVs (PEV) do not cause toxicity, damage, or inflammation in naïve mice. PEV administered during the innate immune response significantly reduces myocarditis with fewer epidermal growth factor (EGF)-like module-containing mucin-like hormone receptor-like 1 (F4/80) macrophages, T cells (cluster of differentiation molecules 4 and 8, CD4 and CD8), and mast cells, and improved cardiac function. Innate immune mediators known to increase myocarditis are decreased by innate PEV treatment including Toll-like receptor (TLR)4 and complement. PEV also significantly reduces perivascular fibrosis and remodeling including interleukin 1 beta (IL-1β), transforming growth factor-beta 1, matrix metalloproteinase, collagen genes, and mast cell degranulation. PEV given at days 7–9 after infection reduces myocarditis and improves cardiac function. MicroRNA (miR) sequencing reveals that PEV contains miRs that decrease viral replication, TLR4 signaling, and T-cell activation. These data show that EVs from the platelets of healthy individuals can significantly reduce myocarditis and improve cardiac function.

Original language	English (US)
Journal	Small
DOIs	https://doi.org/10.1002/smll.202303317
State	Accepted/In press - 2023

Keywords

TLR4
cardiomyopathy
complement
microRNA
regenerative medicine

ASJC Scopus subject areas

Biotechnology
Chemistry(all)
Biomaterials
Materials Science(all)
Engineering (miscellaneous)

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10.1002/smll.202303317

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Beetler, D. J., Bruno, K. A., Watkins, M. M., Xu, V., Chekuri, I., Giresi, P., Di Florio, D. N., Whelan, E. R., Edenfield, B. H., Walker, S. A., Morales-Lara, A. C., Hill, A. R., Jain, A., Auda, M. E., Macomb, L. P., Shapiro, K. A., Keegan, K. C., Wolfram, J., Behfar, A., ... Fairweather, D. L. (Accepted/In press). Reconstituted Extracellular Vesicles from Human Platelets Decrease Viral Myocarditis in Mice. Small. https://doi.org/10.1002/smll.202303317

Beetler, DJ, Bruno, KA, Watkins, MM, Xu, V, Chekuri, I, Giresi, P, Di Florio, DN, Whelan, ER, Edenfield, BH, Walker, SA, Morales-Lara, AC, Hill, AR, Jain, A, Auda, ME, Macomb, LP, Shapiro, KA, Keegan, KC, Wolfram, J, Behfar, A, Stalboerger, PG, Terzic, A, Farres, H, Cooper, LT & Fairweather, DL 2023, 'Reconstituted Extracellular Vesicles from Human Platelets Decrease Viral Myocarditis in Mice', Small. https://doi.org/10.1002/smll.202303317

@article{b3430ada1f114bc78733daa88a7497d8,

title = "Reconstituted Extracellular Vesicles from Human Platelets Decrease Viral Myocarditis in Mice",

abstract = "Patients with viral myocarditis are at risk of sudden death and may progress to dilated cardiomyopathy (DCM). Currently, no disease-specific therapies exist to treat viral myocarditis. Here it is examined whether reconstituted, lyophilized extracellular vesicles (EVs) from platelets from healthy men and women reduce acute or chronic myocarditis in male mice. Human-platelet-derived EVs (PEV) do not cause toxicity, damage, or inflammation in na{\"i}ve mice. PEV administered during the innate immune response significantly reduces myocarditis with fewer epidermal growth factor (EGF)-like module-containing mucin-like hormone receptor-like 1 (F4/80) macrophages, T cells (cluster of differentiation molecules 4 and 8, CD4 and CD8), and mast cells, and improved cardiac function. Innate immune mediators known to increase myocarditis are decreased by innate PEV treatment including Toll-like receptor (TLR)4 and complement. PEV also significantly reduces perivascular fibrosis and remodeling including interleukin 1 beta (IL-1β), transforming growth factor-beta 1, matrix metalloproteinase, collagen genes, and mast cell degranulation. PEV given at days 7–9 after infection reduces myocarditis and improves cardiac function. MicroRNA (miR) sequencing reveals that PEV contains miRs that decrease viral replication, TLR4 signaling, and T-cell activation. These data show that EVs from the platelets of healthy individuals can significantly reduce myocarditis and improve cardiac function.",

keywords = "TLR4, cardiomyopathy, complement, microRNA, regenerative medicine",

author = "Beetler, {Danielle J.} and Bruno, {Katelyn A.} and Watkins, {Molly M.} and Vivian Xu and Isha Chekuri and Presley Giresi and {Di Florio}, {Damian N.} and Whelan, {Emily R.} and Edenfield, {Brandy H.} and Walker, {Sierra A.} and Morales-Lara, {Andrea C.} and Hill, {Anneliese R.} and Angita Jain and Auda, {Matthew E.} and Macomb, {Logan P.} and Shapiro, {Kathryn A.} and Keegan, {Kevin C.} and Joy Wolfram and Atta Behfar and Stalboerger, {Paul G.} and Andre Terzic and Houssam Farres and Cooper, {Leslie T.} and Fairweather, {De Lisa}",

note = "Funding Information: The authors thank the Dennis Dickson Histology Group for their work embedding and staining slides for this project. This group includes Dennis W. Dickson, Linda Rousseau, Virginia Phillips, Ariston Libraro, and Monica Castanedes. The authors also thank the Mayo Microscopy and Cell Analysis Core for experimental and technical support. This work was partially supported by the Mayo Clinic Center for Regenerative Medicine in Florida (D.F. and J.W.), the Mayo Clinic Center for Biomedical Discovery (J.W.), National Institutes of Health (NIH) TL1 TR002380 (D.J.B., D.N.D., E.R.W., and D.F.), National Institute of Allergy and Infectious Diseases under award numbers R21 AI152318 (D.F. and J.W.), R21 AI145356 (D.F.), R21 AI154927 (D.F.), R21 AI163302 (K.A.B.), National Heart Lung and Blood Institute under award number R01 HL164520 (D.F.), the American Heart Association under award number 20TPA35490415 (D.F. and J.W.), the American Heart Association under award number 23SCEFIA1153413 (K.A.B.), and The University of Queensland (J.W.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies. Publisher Copyright: {\textcopyright} 2023 The Authors. Small published by Wiley-VCH GmbH.",

year = "2023",

doi = "10.1002/smll.202303317",

language = "English (US)",

journal = "Small",

issn = "1613-6810",

publisher = "Wiley",

}

TY - JOUR

T1 - Reconstituted Extracellular Vesicles from Human Platelets Decrease Viral Myocarditis in Mice

AU - Beetler, Danielle J.

AU - Bruno, Katelyn A.

AU - Watkins, Molly M.

AU - Xu, Vivian

AU - Chekuri, Isha

AU - Giresi, Presley

AU - Di Florio, Damian N.

AU - Whelan, Emily R.

AU - Edenfield, Brandy H.

AU - Walker, Sierra A.

AU - Morales-Lara, Andrea C.

AU - Hill, Anneliese R.

AU - Jain, Angita

AU - Auda, Matthew E.

AU - Macomb, Logan P.

AU - Shapiro, Kathryn A.

AU - Keegan, Kevin C.

AU - Wolfram, Joy

AU - Behfar, Atta

AU - Stalboerger, Paul G.

AU - Terzic, Andre

AU - Farres, Houssam

AU - Cooper, Leslie T.

AU - Fairweather, De Lisa

N1 - Funding Information: The authors thank the Dennis Dickson Histology Group for their work embedding and staining slides for this project. This group includes Dennis W. Dickson, Linda Rousseau, Virginia Phillips, Ariston Libraro, and Monica Castanedes. The authors also thank the Mayo Microscopy and Cell Analysis Core for experimental and technical support. This work was partially supported by the Mayo Clinic Center for Regenerative Medicine in Florida (D.F. and J.W.), the Mayo Clinic Center for Biomedical Discovery (J.W.), National Institutes of Health (NIH) TL1 TR002380 (D.J.B., D.N.D., E.R.W., and D.F.), National Institute of Allergy and Infectious Diseases under award numbers R21 AI152318 (D.F. and J.W.), R21 AI145356 (D.F.), R21 AI154927 (D.F.), R21 AI163302 (K.A.B.), National Heart Lung and Blood Institute under award number R01 HL164520 (D.F.), the American Heart Association under award number 20TPA35490415 (D.F. and J.W.), the American Heart Association under award number 23SCEFIA1153413 (K.A.B.), and The University of Queensland (J.W.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies. Publisher Copyright: © 2023 The Authors. Small published by Wiley-VCH GmbH.

PY - 2023

Y1 - 2023

N2 - Patients with viral myocarditis are at risk of sudden death and may progress to dilated cardiomyopathy (DCM). Currently, no disease-specific therapies exist to treat viral myocarditis. Here it is examined whether reconstituted, lyophilized extracellular vesicles (EVs) from platelets from healthy men and women reduce acute or chronic myocarditis in male mice. Human-platelet-derived EVs (PEV) do not cause toxicity, damage, or inflammation in naïve mice. PEV administered during the innate immune response significantly reduces myocarditis with fewer epidermal growth factor (EGF)-like module-containing mucin-like hormone receptor-like 1 (F4/80) macrophages, T cells (cluster of differentiation molecules 4 and 8, CD4 and CD8), and mast cells, and improved cardiac function. Innate immune mediators known to increase myocarditis are decreased by innate PEV treatment including Toll-like receptor (TLR)4 and complement. PEV also significantly reduces perivascular fibrosis and remodeling including interleukin 1 beta (IL-1β), transforming growth factor-beta 1, matrix metalloproteinase, collagen genes, and mast cell degranulation. PEV given at days 7–9 after infection reduces myocarditis and improves cardiac function. MicroRNA (miR) sequencing reveals that PEV contains miRs that decrease viral replication, TLR4 signaling, and T-cell activation. These data show that EVs from the platelets of healthy individuals can significantly reduce myocarditis and improve cardiac function.

AB - Patients with viral myocarditis are at risk of sudden death and may progress to dilated cardiomyopathy (DCM). Currently, no disease-specific therapies exist to treat viral myocarditis. Here it is examined whether reconstituted, lyophilized extracellular vesicles (EVs) from platelets from healthy men and women reduce acute or chronic myocarditis in male mice. Human-platelet-derived EVs (PEV) do not cause toxicity, damage, or inflammation in naïve mice. PEV administered during the innate immune response significantly reduces myocarditis with fewer epidermal growth factor (EGF)-like module-containing mucin-like hormone receptor-like 1 (F4/80) macrophages, T cells (cluster of differentiation molecules 4 and 8, CD4 and CD8), and mast cells, and improved cardiac function. Innate immune mediators known to increase myocarditis are decreased by innate PEV treatment including Toll-like receptor (TLR)4 and complement. PEV also significantly reduces perivascular fibrosis and remodeling including interleukin 1 beta (IL-1β), transforming growth factor-beta 1, matrix metalloproteinase, collagen genes, and mast cell degranulation. PEV given at days 7–9 after infection reduces myocarditis and improves cardiac function. MicroRNA (miR) sequencing reveals that PEV contains miRs that decrease viral replication, TLR4 signaling, and T-cell activation. These data show that EVs from the platelets of healthy individuals can significantly reduce myocarditis and improve cardiac function.

KW - TLR4

KW - cardiomyopathy

KW - complement

KW - microRNA

KW - regenerative medicine

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U2 - 10.1002/smll.202303317

DO - 10.1002/smll.202303317

M3 - Article

AN - SCOPUS:85168623342

JO - Small

JF - Small

SN - 1613-6810

ER -

Reconstituted Extracellular Vesicles from Human Platelets Decrease Viral Myocarditis in Mice

Abstract

Keywords

ASJC Scopus subject areas

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